Potential health effects of gasoline and its constituents: A review of current literature (1990-1997) on toxicological data.

We reviewed toxicological studies, both experimental and epidemiological, that appeared in international literature in the period 1990-1997 and included both leaded and unleaded gasolines as well as their components and additives. The aim of this overview was to select, arrange, and present references of scientific papers published during the period under consideration and to summarize the data in order to give a comprehensive picture of the results of toxicological studies performed in laboratory animals (including carcinogenic, teratogenic, or embryotoxic activity), mutagenicity and genotoxic aspects in mammalian and bacterial systems, and epidemiological results obtained in humans in relation to gasoline exposure. This paper draws attention to the inherent difficulties in assessing with precision any potential adverse effects on health, that is, the risk of possible damage to man and his environment from gasoline. The difficulty of risk assessment still exists despite the fact that the studies examined are definitely more technically valid than those of earlier years. The uncertainty in overall risk determination from gasoline exposure also derives from the conflicting results of different studies, from the lack of a correct scientific approach in some studies, from the variable characteristics of the different gasoline mixtures, and from the difficulties of correctly handling potentially confounding variables related to lifestyle (e.g., cigarette smoking, drug use) or to preexisting pathological conditions. In this respect, this paper highlights the need for accurately assessing the conclusive explanations reported in scientific papers so as to avoid the spread of inaccurate or misleading information on gasoline toxicity in nonscientific papers and in mass-media messages.

The co-operative action of hyaluronidase and urokinase on the isoproterenol-induced myocardial infarction in rats.

The effects of the intravenous administration of hyaluronidase (HY; 2,500 IU/kg) and urokinase (UK; 20,000 and 40,000 IU/kg), alone or in combination, on the isoproterenol (ISP) induced myocardial infarction (MI) in rats, were studied. The severity of infarction was determined by measuring the levels of serum enzymes (CPK, GOT, LDH) and by evaluating the extent of the injured areas and the incidence of mortality. Plasma thromboxane B2 (TXB2) levels were also determined. All the treatments reduced the infarction area and the enzyme levels (increased by ISP) to a varying degree. However, a definite potentiating activity was obtained when HY was combined with the highest dose of UK. This combination was also capable of reducing the mortality rate. Finally, both HY and UK or the combined preparation brought the plasma TXB2 levels back to normal. These findings suggest the possibility of complementary activities of HY and UK in the treatment of experimental MI.

"In vitro" activity of urokinase on platelet function and on ADP degradation by vascular tissue.

The effects of urokinase on ADP breakdown by vessel-wall, platelet aggregation and the related prostaglandin system "in vitro" were investigated. It is confirmed that urokinase does not induce platelet aggregation both in humans and rabbits "in vitro". Conversely, in high concentrations, urokinase inhibits ADP-induced platelet aggregation in human and rabbit platelet-rich plasma. No effects were observed on rabbit platelet thromboxane A2 release and on rat vascular prostacyclin production, both measured by radioimmunoassay of thromboxane B2 and 6-keto-F1 alpha prostaglandin, respectively. Moreover, the incubation of urokinase with vascular endothelium resulted in an increased disappearance rate.

Cisplatin triggers platelet activation.

Clinical observations suggest that anticancer drugs could contribute to the thrombotic complications of malignancy in treated patients. Thrombotic microangiopathy, myocardial infarction, and cerebrovascular thrombotic events have been reported for cisplatin, a drug widely used in the treatment of many solid tumours. The aim of this study is to explore in vitro cisplatin effect on human platelet reactivity in order to define the potentially active role of platelets in the pathogenesis of cisplatin-induced thrombotic complications. Our results demonstrate that cisplatin increases human platelet reactivity (onset of platelet aggregation wave and thromboxane production) to non-aggregating concentrations of the agonists involving arachidonic acid metabolism. Direct or indirect activation of platelet phospholipase A(2) appears to be implicated. This finding contributes to a better understanding of the pathogenesis of thrombotic complications occurring during cisplatin-based chemotherapy.

The vascular protection of ditazole and its effect on arachidonic acid metabolism.

Ditazole (4,5-diphenyl-2-bis-(2-hydroxyethyl)-aminoxazol) is a weak anti-inflammatory drug and has been shown to inhibit thrombus formation following electrically stimulated vascular damage in the microcirculation of the hamster cheek pouch. The drug was found to inhibit thromboxane A2 (TXA2) production ex vivo as determined by radioimmunoassay (RIA) and to reversibly antagonise the effect of TXA2 on smooth vascular tissue. However, in contrast to acetylsalicylic acid (ASA), it does not inhibit vessel cyclooxygenase. The apparent vascular protective effect of ditazole could not be ascribed to an enhanced production of vascular prostacyclin (PGI2) since the latter, when estimated ex vivo by RIA, was not enhanced following oral treatment with the drug. It is suggested that the mode-of-action of ditazole may be different from the cyclo-oxygenase/PG synthetase blocking action of most other non-steroidal anti-inflammatory drugs.

An in vitro method for evaluating vascular endothelial ADPase activity.

Some xenobiotics, known to promote the development of thrombotic phenomena, affect vascular endothelium ADPase, a regulatory enzyme that inactivates vaso- and platelet-active adenine nucleotides. This proposed new experimental approach represents an improved method of evaluation of vascular endothelial ADPase activity which is assessed by measuring, at pre-established times, the degradation rate of exogenous ADP incubated with aortic bovine patches. The ADP dosage was performed by using a spectrophotometric enzymatic assay. Statistical analyses showed that the method is capable of highlighting the linearity of the ADPase activity time-course, thus indicating that the slopes of time-degradation curves of ADP are a valid index for this endothelial ectoenzyme activity. Results obtained with ADPase inhibiting or stimulating agent confirm that this in vitro method is an efficient tool for estimating the ability of xenobiotics or drugs to modify the nonthrombogenic properties of vascular endothelium.

Dermatan sulfate versus unfractionated heparin for the prevention of venous thromboembolism in patients undergoing surgery for cancer. A cost-effectiveness analysis.

BACKGROUND: In a recent clinical trial, dermatan sulfate was found to be more effective than unfractionated heparin (UFH), but equally well tolerated, for the prevention of deep vein thrombosis (DVT) after major surgery for cancer. OBJECTIVE: To perform a cost-effectiveness analysis of dermatan sulfate versus UFH in this clinical setting. DESIGN AND SETTING: This was a retrospective economic analysis using data from a randomised clinical trial, and was performed from the hospital perspective. METHODS: Clinical event rates were extrapolated from the observed venographic DVT rates, using appropriate assumptions from the scientific literature. The economic effects of switching DVT prophylaxis from UFH to dermatan sulfate and the potential lives saved were assessed by a predictive decision model. RESULTS: The per patient cost, including the burden of residual thromboembolic events and major bleeding complications, was estimated to be 154 euros (EUR) for dermatan sulfate and EUR185 for UFH (1998 values). With reference to a potential target population of 60,000 patients/year undergoing surgery for cancer in Italy, the total prophylaxis-associated cost was EUR9,258,000 for dermatan sulfate and EUR11,096,000 for UFH, whereas the potential deaths from prophylaxis failure were 204 and 392, respectively. This represented a saving of EUR1,838,000 and 188 potential lives per year with the dermatan sulfate option. The final costs and effects were mainly sensitive to variations in the rates of DVT and pulmonary embolism, and to the possible need for 1 extra day of hospitalisation because of the earlier preoperative initiation of dermatan sulfate prophylaxis. CONCLUSION: Dermatan sulfate is more cost effective than UFH for the prevention of postoperative venous thromboembolism in patients with cancer. If the hospital stay needs to be prolonged, then the dermatan sulfate option may involve a small additional cost (EUR47) per potential life saved.

Sex-related toxicity of somatostatin and its interaction with pentobarbital and strychnine.

The intravenous LD50 of the hypothalamic tetradecapeptide somatostatin was determined in mice and rats of both sexes. It was found that somatostatin has a sex-related toxicity both in mice and rats. The interaction of low and high doses of peptide with the LD50s of two central nervous system (CNS) drugs, namely pentobarbital and strychnine, was also studied in male and female mice. Differential effects were observed as follows: a very low dose (0.1 mg/kg) of somatostatin does not affect the toxicity of these compounds, whereas the injection of 1 mg/kg of peptide increased pentobarbital toxicity and decreased the toxicity of strychnine. However, an increase in the toxicity of both substances was obtained with very high non-lethal doses of peptide (20 and 30 mg/kg, in female and male mice, respectively).

Cocaine toxic effect on endothelium-dependent vasorelaxation: an in vitro study on rabbit aorta.

Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert-butylhydroquinone, a sarcoplasmic Ca2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca2+-ATPase pump.

Effects of phosvitin on the ecg changes induced under hypoxia in the rat.

The effect of phosvitin (1 g kg(-1), i.p.) on ecg changes induced in rats by a reduction of partial oxygen pressure in the respiratory mixture was studied. Phosphocreatine, phosphoserine, ATP and Na2HPO42H2O were also administered intraperitoneally for comparison. Phosvitin alone was found to prevent the hypoxia-induced T-wave changes (flattening or disappearance), which were also temporarily aggravated by injection of noradrenaline. As to the metabolic, hypoxia-induced myocardial changes, two hypotheses are discussed: a release of phosvitin phosphate radicals ready for immediate utilization or a drug action mediated via a membrane-bound intrinsic proteinkinase system.

A simple method for ex vivo evaluation of biomaterial interaction with blood platelets.

The process of thrombus formation, as a consequence of the interaction of artificial surfaces with blood, is related to the activation of blood platelets. A simple ex vivo method, which is suitable for the evaluation of the platelet-surface interaction is described. This method has been used to compare the haemocompatibility of several artificial materials, including nylon-6, Silastic and pyrolytic carbon.

A native whole blood test for the evaluation of blood-surface interaction: determination of thromboxane production.

The method developed to evaluate the hemocompatibility of artificial materials involves the determination of thromboxane production during the clotting of rabbit blood, in test tubes of different materials. The concentration of serum TXB2 obtained after incubation of whole blood in glass test tubes, for 40 min at 37 degrees C, averaged 416.8 +/- 23.3 ng/ml (mean +/- SE). Polymethylpentene, recognised as having a relatively poor blood compatibility, elicited 309.5 +/- 17.2 ng/ml of serum TXB2, while silicone and Avcothane, considered of better hemocompatibility, showed thromboxane levels of 276.2 +/- 28.2 and 222.9 +/- 31.5 ng/ml, respectively. These values validate the usefulness of the proposed method as a preliminary in vitro screening test of artificial materials intended for biomedical application.

Clinical and economic outcomes of pneumonia in children: a longitudinal observational study in an Italian paediatric hospital.

RATIONALE, AIMS AND OBJECTIVES: Antibiotic prescription for acute lower respiratory infections (ALRI) in hospitalized children can have a major impact on cure and costs. We performed a longitudinal study to explore the appropriateness of prescriptions, the predictors of therapeutic patterns, and the main outcomes: readmission, length of stay (LOS) and costs. METHODS: Ninety-nine children who were inpatients of a paediatric hospital receiving antibiotic treatment for community acquired ALRI were consecutively enrolled. To calculate the costs of pneumonia treatment, we collected data on clinical presentation and resources consumption. We used multiple regression analysis to identify predictors of LOS and choice of therapy, and one-way ANOVA to evaluate cost differences among treatment groups. RESULTS: Parenteral antibiotics were administered in 64.6% of cases, whereas 35.4% received oral antibiotic therapy by itself (OAT). Switch therapy (SWT) was performed in 43.4% of cases. The most frequently prescribed antibiotic for parenteral therapy was ceftriaxone (58.3%), and for oral therapy cefprozil (58.1%). The median LOS was 3 days and the cure rate 99% (95%CI: 97-100%). SWT and OAT were significantly associated with a shorter LOS. The clinical variables were not significantly associated with SWT or OAT. The average costs per patient in the management of pneumonia were Euro 1435. SWT or OAT were associated with significant lower costs: Euro 1487 per patient (95%CI: 1395-1580) and Euro 1335 per patient (95%CI: 1233-1437), respectively. CONCLUSIONS: The hospital management of paediatric pneumonia was more influenced by the early discharge policy than by clinical variables without under-cure.

[Drugs for the treatment of benign prostatic hypertrophy]. / Farmaci per il trattamento dell'ipertrofia prostatica benigna.

Benign Prostatic Hyperplasia (BPH) usually occurs in males 45-50 old and progressively involves 75% of the male population over 75 years of age. The clinical manifestations of BPH are related primarily to bladder outlet obstructions resulting from enlargement (mechanical component) of the prostate gland, and from extrinsic and intrinsic sympathetic activation of alpha-adrenoceptors (dynamic component) present in the prostatic muscle tissue, prostatic urethra, bladder base and neck. Several drugs have been employed in the last decades: LHRH analogs (Leuprorelin and Goserelin) which can reduce the testicular production of androgens with reduction in prostate size; Serenoa repens for its anti-androgenic and anti-estrogenic activities; Finasteride (5-alpha-reductase inhibitor) which blocks the conversion of testosterone into the more active dihydrotestosterone. Finally, the alpha 1 blocking agents (Terazosin, Doxazosin, Tamsulosin) that improve urinary symptoms by acting on dynamic component. Clinical improvements derive from their antagonist action on alpha 1 adrenergic receptors which mediate contraction of the prostate gland, proximal urethra, bladder base and neck, with the consequent reduction of urethral pressure, bladder outlet resistance, and increase of urinary flow. Due to its pharmacodynamic and pharmacokinetic properties, as well as the clinical results obtained, Terazosin, alpha 1 blocker, appears to be particularly useful in the treatment of patients with mild- to moderate symptomatic BPH.

[Evaluation model of the effect of Rofecoxib on the co-prescription of gastroprotective agents observed during the treatment of osteoarthritis]. / Modello valutativo dell'effetto sulla co-prescrizione di gastroprotettori osservato durante il trattamento dell'artrosi con Rofecoxib.

OBJECTIVE: This study was conducted to define an evaluation model to estimate changes in the co-prescription of gastroprotective agents (GPAs) induced by rofecoxib in the treatment of osteoarthritis (OA). METHODS: On the basis of a cross-linking information, which were stored in different administrative and clinical databases, a multivariate regression analysis was used to develop the model. Data were collected by 30 general practitioners of the Local Health Unit of Ravenna (middle-north of Italy). RESULTS: The study population consisted of 2,944 patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) and 487 treated with rofecoxib. Patients treated with rofecoxib generally presented a higher number of gastrointestinal damage risk factors and also a lower level of GPAs co-prescription compared to those treated with NSAIDs. Including in the model variables such as type of anti-inflammatory treatment (NSAIDs or rofecoxib), gender, age by class, previous hospital admissions due to gastrointestinal complications, number of different NSAIDs used, and prescription of corticosteroids, the regression equation and its coefficients were identified. A non-linear relationship between the percentage of patients treated with rofecoxib and the relative reduction of GPAs co-prescription was found. It has been estimated the basis of the registered percentage of patients treated with rofecoxib (17,6%) adjusting for gastrointestinal damage risk factors, and on a 63% (CI95%: 55%-70%) relative reduction of GPA use with rofecoxib with respect to NSAIDs was estimated. CONCLUSIONS: Based on data collected in the clinical practice after the introduction of rofecoxib, a model evaluating the relationship between the frequency of its use in the OA population and the expected reduction of GPAs, has been developed.

Toxicological aspects of dimethyl-ether.

The authors report the results of a series of investigations on the toxic effects produced in mice and rabbits by inhalation of Dimethyl-ether. Median lethal concentration (LC50) and Median lethal time (LT50) were determined in the mouse. Also the effects of DME inhalation on some physiological parameters (blood pressure, heart rate, blood gas and pH data) were evaluated in the rabbit.

Prostacyclin effects on the blood pressure responses to norepinephrine in rats treated with aspirin or indomethacin.

The atherosclerotic condition is associated with a reduction of PGI2 synthesis; moreover, in the presence of elevated serum cholesterol levels, pressor responses to norepinephrine are potentiated. In order to verify if a complete inhibition of PGI2 production affects the vascular reactivity, it was assayed two cycloxygenase inhibitors (lysine acetylsalicylate and indomethacin) in rats. The two drugs significantly potentiated the blood pressure responses to norepinephrine, and completely inhibited PGI2-like substances production by arterial rings. The prostacyclin infusion (15 ng/kg/min, i.v.) completely reversed such potentiation, without any major modification in the basal blood pressure values. These results show that PGI2 production is responsible for vascular tone modulation and may partially explain the altered vascular reactivity in the atherosclerotic condition.

Bioassay for thymic extracts: guinea pig spleen lymphocytes-rabbit red blood cells rosette method.

An assay is described for assessing the potency of thymic extracts by the capacity of guinea pig spleen lymphocytes to form rosettes with rabbit red blood cells. Its sensitivity and reproducibility have been evaluated by statistical analysis of the data obtained testing different batches of the calf thymus extract TP-1.